Mitochondrial aldehyde dehydrogenase-2 (ALDH2) is an enzyme that catalyzes the conversion of conversion of xenogenic and biogenic aldehydic compounds to corresponding acids, such as acetaldehyde to acetic acid. ALDH2 is critical for alcohol metabolism in humans because it further breaks down the product of ethanol oxidation from alcohol dehydrogenase activity. The 56 kDa enzyme is encoded in the nuclear genome and is transported into mitochondria. ALDH2 exists in solution as a tetrameric protein composed of four identical subunits, each consisting of approximately 517 amino acid residues. The tetramer can be regarded as a dimer of dimers. The interface between monomers that form a dimer is different and more extensive than the interface between the two dimers that form the tetramer. Each subunit is composed of three domains: the catalytic domain, the coenzyme or NAD+-binding domain, and the oligomerization domain.
Fanconi anemia (FA) is an autosomal recessive disorder characterized by congenital abnormalities, bone marrow failure, and a predisposition to malignancies, including myelodysplastic syndrome and acute myelogenous leukemia. See Auerbach, et al., In: The Metabolic and Molecular Basis of Inherited Diseases. 8th Ed. Scriver, et al., editors. New York: McGraw-Hill; 2001. pp. 753-768. Most patients experience bone marrow failure at a median age of five years. Progressive pancytopenia and congenital malformations, including short stature, radial aplasia, urinary tract abnormalities, hyperpigmentation, and developmental delay are common symptoms. Fanconi Anemia is associated with a predisposition to cancer, particularly acute myeloid leukemia and an increased risk of developing solid tumors.
Testing for Fanconi anemia is indicated in young patients with aplastic anemia, arm and/or thumb, cardiac, central nervous system, genitourinary, kidney, and/or skeletal system anomalies, hyper-pigmentation, small size, and/or bleeding disorders.
Several FA complementation groups (FA-A through FA-O) have been reported (see, e.g., Joenje, et al., Am J Hum Genet. (2000), 67:759-762), with FA-A (Online Mendelian Inheritance in Man, OMIM no. 227650) constituting approximately two-thirds of the patients. The FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (BRIP1), FANCL, FANCM, FANCN (PALB2) and FANCO (RAD51C) genes have been cloned and known to be the causative mutations of Fanconi Anemia. See, e.g., Lo Ten Foe, et al. Nat Genet. (1996), 14:320-323; Fanconi Anemia/Breast Cancer Consortium. Nat Genet. (1996), 14:324-328; Strathdee, et al. Nat Genet. (1992), 1:196-198; de Winter, et al. Am J Hum Genet. (2000), 67:1306-1308; de Winter, et al. Nat Genet. (2000), 24:15-16; and de Winter, et al. Nat Genet. (1998), 20:281-283. However, the specific function of these genes remains unclear.
The FA gene products play an important role in protecting the integrity of the human genome; mutations in any of the FA genes always lead to genomic instability due to failure to repair DNA damage. Over the last decade, the role for Fanconi Anemia gene products in DNA repair has been established. However, the source and chemical agents that cause excessive genomic instability leading to the phenotype of developmental abnormality, BMF, and predisposition malignancy in FA patients had been elusive. Environmental pollutants, carcinogens, and biogenic reactive chemical species that are capable of attacking DNA and causing genome instability under physiological conditions were the prime suspects of the molecular triggers of FA. Reactive aldehydes are known toxic molecules that can damage DNA by forming DNA-protein or DNA-DNA crosslinking. See Brooks, P. J. and Zakhari, S. Acetaldehyde and the genome: Beyond nuclear DNA adducts and carcinogenesis, Environ. Mol. Mutagen., 2014, 55: 77-91. It has been proposed that bone marrow failure in FA patients could result from endogenous aldehyde induced toxicity, which then leads to the depletion of hematopoietic stem cells (HSCs), as was observed in Aldh2−/−Fancd2−/− mice. See Langevin F, et al. Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice, Nature (2011), 475(7354):53-58; Garaycoechea J I, et al. Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function. Nature (2012), 489 (7417):571-575. The ALDH2 genotype of a group of Japanese FA patients has recently been deciphered. See Hira A, et al. Variant ALDH2 is associated with accelerated progression of bone marrow failure in Japanese Fanconi anemia patients, Blood (2013), 122(18):3206-3209. In one study involving Japanese patient population, dramatic acceleration of bone marrow failure and increased frequency of malformation in some tissues was observed with ALDH2 deficiency (these patients carried double mutations in ALDH2 gene, i.e., homozygous mutant allele represented as ALDH*2/*2, thus, entirely devoid of ALDH2 activity). See Hira (2013). Most strikingly, those patients entirely deficient for ALDH2 developed bone marrow failure within the first 7 months of life, suggesting that reactive aldehydes play an important role in Fanconi Anemia prognosis. See id.
The current disclosure provides compounds that are agonists of ALDH2, useful for treating and/or preventing diseases or disorders in which ALDH2 plays a role. For example, the compounds of the invention may be useful to treat Peripheral Artery Disease (PAD), Acute Inflammatory Pain, liver injury and damage such as liver fibrosis, alcohol-related disorders such as intolerance, addiction, intoxication, abuse, etc. Further, the compounds of the invention may be useful to treat Fanconi Anemia. The current disclosure also provides methods for treating and/or preventing cancer, for example, esophageal cancer and cancer in patients with Fanconi Anemia or those carrying a FANC* causative mutation for Fanconi Anemia, as well as prevention and/or protection against injuries and damages caused by ionized radiation or chemotherapy.